DE4229903A1 - New acetals of ketophosphamide and alkyl glycosides - Google Patents

Abstract

New acetals of ketophosphamide and alkylglycoside have the general formula (I), in which R1, R2, R3, R4, R5, R6, R7 and R8 have the meaning given in the description. Also disclosed is a process for preparing the same and their use as highly selective cytostatic agents in cancer therapy.

Description

The present invention relates to new acetals of ketophosphamide and Alkylglycosides, processes for their preparation and their use as highly selective cytostatics in cancer therapy.

Malignant cells are known to increase one over normal tissue Show glycolysis and thus lactate production and the pH value in the tumor tissue be reduced by intravenously administered glucose (see S. Tanneberger, Experimental and clinical tumor chemotherapy; General tumor chemothera pie; G. Fischer Verlag, Stuttgart / New York 1980; Natural sciences 46, 2 (1959); Cancer Res. 42, 1498 (1982); 42, 1505 (1982)).

In the past attempts have been made to compensate for these differences in pH between nor to use malem and tumor tissue for a selective tumor therapy (cf. Liebigs Ann. Chem. 1987, 847-856; Tetrahedron Lett. 22 (1981) 239-242). It was alkylating compounds which have been attempted because of insufficient differences differentiation between healthy and malignant tissue a very low therapeutic cal width to convert into non-toxic, acid-labile prodrug forms that only in tumor tissue due to the lower pH prevailing there be cleaved selectively to form an active, alkylating cytostatic. On in this way, selective tumor therapy should be sought.

It had been shown, however, that the reference in the above-mentioned reference compounds were not found to be so acid labile as to be selective in Tumor tissue was cleaved back to the active cytocidal agent.  

It has now surprisingly been found that the following Ver Bindings are non-toxic, while in the tumor tissue caused by Hypergly kaem achievable pH value converted into cytocidal compounds by hydrolysis can be.

The present invention relates to new acetals of ketophosphamide and alkylgly cosides of the general formula (I),

in which
R ¹ , R ² , R ³ and R ^{4 are} identical or different and represent hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or a hydroxyl protective group,
R ^{5 represents} straight-chain or branched alkyl having up to 8 carbon atoms,
R ^{6 represents} straight-chain or branched alkyl having up to 8 carbon atoms,
R ⁷ and R ^{8 are the} same or different and represent hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by chlorine,
and wherein the sugar residue stands for aldohexoses and the corresponding pyranosides and can be present in the D or L form and with an α or β configuration at the anomeric center.

Hydroxy protective group in the context of the definition given above is in general mean for a protective group from the series: tert.Butoxydiphenylsilyl, Trimethylsi lyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, Triphenylsilyl, trimethylsilylethoxycarbonyl, benzyl, benzyloxycarbonyl, 2-nitro benzyl, 4-nitrobenzyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, tert. Butyloxycarbonyl, allyloxycarbonyl, 4-methoxybenzyl, 4-methoxybenzyloxycarbo nyl, formyl, acetyl, trichioracetyl, 2,2,2-trichloroethoxycarbonyl, 2,4-dimethoxy benzyl, 2,4-dimethoxybenzyloxycarbonyl, methylthiomethyl, methoxyethoxy methyl, [2- (trimethylsilyl) ethoxy] methyl, 2- (methylthiomethoxy) ethoxycarbonyl, Benzoyl, 4-methylbenzoyl, 4-nitrobenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl or 4-methoxybenzoyl. Acetyl, benzoyl, benzyl or methylbenzyl are preferred.

Aldohexoses stands for example for D - (+) - glucose, L - (-) - glucose, D - (+) - manno se, L - (-) - mannose, D - (+) - galactose and L - (-) - galactose. The preferred is here D - (-) - glucose.

Compounds of the general formula (I) are preferred
in which
R ¹ , R ² , R ³ and R ^{4 are the} same or different and represent hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or acetyl, benzyl or benzoyl,
R ^{5 represents} straight-chain or branched alkyl having up to 6 carbon atoms,
R ^{6 represents} straight-chain or branched alkyl having up to 6 carbon atoms,
R ⁷ and R ^{8 are the} same or different and represent hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by chlorine
and wherein the sugar residue stands for aldohexoses and the corresponding pyranosides and can be present in the D or L form and with an α or β configuration at the anomeric center.

Compounds of the general formula (I) are particularly preferred
in which
R ¹ , R ² , R ³ and R ^{4 are the} same or different and represent hydrogen, straight-chain or branched alkyl having up to 3 carbon atoms or acetyl, benzyl or benzoyl,
R ^{5 represents} straight-chain or branched alkyl having up to 4 carbon atoms,
R ^{6 represents} straight-chain or branched alkyl having up to 4 carbon atoms,
R ⁷ and R ^{8 are the} same or different and represent hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by chlorine,
and wherein the sugar residue stands for aldohexoses and the corresponding pyranosides and can be present in the D or L form and with an α or β configuration at the anomeric center.

Compounds of the general formula (I) are very particularly preferred,
in which
R ¹ , R ² , R ³ and R ^{4 are} identical or different and represent hydrogen, methyl, ethyl or acetyl,
R ^{5 represents} methyl or ethyl,
R ^{6 represents} methyl,
R ⁷ and R ^{8 represent} hydrogen
and wherein the sugar residue stands for D-glucose with an α or β configuration at the anomeric center.

In addition, a method for producing the compounds according to the invention gene of the general formula (I) found, characterized in that Compounds of the general formula (II)

in which
R ^{1 '} , R ^2' , R ^{3 '} and R ^{4' have} the meaning given above of R ¹ , R ² , R ³ and R ⁴ , but do not represent hydrogen
and
R ⁵ and R ^{6 have} the meaning given above,
with N, N-bis (2-chloroethyl) phosphoric acid amide dichloride of the formula (III)

Cl ₂ P (O) N (CH ₂ CH ₂ Cl) ₂ (III)

in inert solvents, in the presence of a base and an auxiliary,
then carries out ammonolysis,
and in the event that R ⁷ and / or R ^{8 are} not hydrogen, the remaining substituents listed above are introduced by customary methods,
and in a last step, optionally by releasing the protective group R ^{2 '} , R ^3' , R ^{4 '} and / or R ^1', releases the hydroxyl functions.

The method according to the invention can be exemplified by the following formula are explained:

Suitable solvents are the usual organic solvents, which are among the Do not change reaction conditions. These preferably include ethers such as Di ethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons  such as benzene, toluene, xylene, hexane, cyclohexane, petroleum fractions, or halogens Hydrogen oils such as dichloromethane, trichloromethane, carbon tetrachloride, dichloro ethylene, trichlorethylene or chlorobenzene, or ethyl acetate, dimethyl sulfoxide, Dimethylformamide, acetonitrile, acetone or nitromethane. It is also possible To use mixtures of the solvents mentioned. Preferred are tetrahydrofuran, Dichloromethane and toluene.

Suitable bases are 1,8-diazabicyclo [5,4,0] undec-7-ene, imidazole, pyridine, tetra zol and the usual organic amines. These preferably include alkylamines such as Triethylamine, diisopropylamine, dicyclohexylamine and ethyldiisopropylamine. Triethylamine, 1,8-diazabicyclo [5,4,0] undec-7-ene and are particularly preferred Pyridine.

N-methylimidazole and dimethylaminopyridine (DMAP) are suitable as auxiliary substances. N-methylimidazole is preferred.

The bases and auxiliaries are generally used in an amount of 1 to 5 mol, preferably from 1 to 1.75 mol, in each case based on 1 mol of the compounds of all general formula (III) used.

The reaction is generally carried out at normal pressure. But it is also possible to carry out the process under positive pressure or under negative pressure (e.g. in a range from 0.5 to 5 bar).

The process according to the invention is generally in a temperature range from 0 ° C to + 60 ° C, preferably carried out at room temperature.

The reaction conditions listed above are also during the ammono lysis not changed. That evaporated by passing the ammonia stream Solvent is replaced during the reaction.

The protective groups on the sugar residue are split off using the customary method in inert solvents in the presence of a base or by hydrogenolysis.  

The usual inorganic bases are suitable as bases for the cleavage. For this preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as Sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali carbonates such as Sodium or potassium carbonate or sodium hydrogen carbonate, or alkali alcohol latex such as sodium ethanolate, sodium methoxide, potassium ethanolate, potassium methoxide or potassium tert-butoxide. Sodium carbonate or are particularly preferred Potassium carbonate used.

Suitable solvents for cleavage are those customary for saponification organic solvents. These preferably include alcohols such as methanol, ethanol, Propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or dioxane, or dimethylformamide or dimethyl sulfoxide. Alko are particularly preferred hole like methanol, ethanol, propanol or isopropanol used. It is the same possible to use mixtures of the solvents mentioned.

The cleavage is generally in a temperature range from 0 ° C to + 60 ° C, preferably from + 20 ° C to + 40 ° C. In general, Ab cleavage carried out at normal pressure. But it is also possible with negative pressure or work at overpressure (e.g. from 0.5 to 5 bar).

The cleavage of special hydroxyl protective groups (silyl and benzyl groups) takes place, for example, with tetrabutylammonium fluoride or by hydrogenolytic cleavage, in the case of the benzyl group in the presence of a catalyst, for example a mixture of palladium / C and palladium / CaCO ₃ , with hydrogen, in one of the The solvents listed above, preferably methanol, in a temperature range from 0 ° C. to 40 ° C., preferably at room temperature.

N, N-bis (2-chloroethyl) phosphoric acid amide dichloride of the formula (III) is known [see. J. Am. Chem. Soc. 76, 655 (1954)].

The compounds of the general formula (II) are new and can be prepared by using glucopyranosides of the general formula (IV)

in which
R ^{1 ′} , R ^{2 ′} , R ^{3 ′} and R ^{4 ′ have} the meaning given above,
first by reaction with enol ethers of the general formula (V)

in which
R ^{5 has} the meaning given above,
R ^{7 represents} one of the silylhydroxy protective groups listed above, preferably tert-butoxy-diphenylsilyl
and
R ^{8 represents} hydrogen (R ⁶ = CH ₃ / formula I), or represents straight-chain or branched C ₁ -C ₇ alkyl, (R ⁶ = C ₂ -C ₇ alkyl / formula I)
in one of the solvents listed above and in the presence of a catalyst and a base in the compounds of the general formula (VI)

in which
R ^{1 ′} , R ^{2 ′} , R ^{3 ′} , R ^{4 ′} , R ⁵ , R ⁶ and R ^{7 have} the meaning given above,
transferred, and in a last step the protective group R ^{7 is} split off by customary methods.

The halogenated hydrocarbons listed above are suitable as solvents special methylene chloride.

The reaction with the enol ethers takes place in a protective gas atmosphere, in one Temperature range from 0 ° C to + 40 ° C, preferably at room temperature and Nor color print.

In addition to the bases listed above, triethylamine is particularly suitable as the base.

Substituted arylsulfonic acids, such as naphthylsulfonic acid, p-toluenesulfonic acid (PTS) or pyridinium-p-toluenesulfonate (PPTS) or C ₁ -C ₄ -alkylsulfonic acids, are generally used as catalysts. Pyri dinium p-toluenesulfonate is preferred.

The catalyst is used in an amount of 0.1 mol to 5 mol, preferably 0.1 mol to 0.5 mol, based on 1 mol of the compounds of the general formula (II) puts.

In addition to the method listed above, desilylation is preferably carried out using tetra-n-butylammonium fluoride / H ₂ O in the presence of tetrahydrofuran and at room temperature.

The compounds of the general formula (IV) and (V) are known or can can be produced by customary methods.

The compounds of general formula (VI) are new and can then according to the procedures listed above.

The compounds according to the invention show an unforeseeable, valuable pharmacological spectrum of action.

The acid labile derivatives of the inactivated Keotphosphamids of the general Formula (I) is a cytostatic that is non-toxic in its transport form. They set at the pH value that can be achieved in the tumor tissue through hyperglycemia hydrolysis releases a cytocidal compound, the Friedman acid.

The kinetic measurements for acid-catalyzed hydrolysis were carried out at 35 ° C in a Varian FT-80A NMR spectrometer. For this purpose, the substances were dissolved in a Sorensen buffer (pH 6.2), in order to increase the solubility, some experiments were also carried out in a 40% d ₈ [1,4-dioxane] / D ₂ O mixture. The relative concentrations of the remaining acetal were determined from the FT-80 NMR spectra by measuring the integral height of the characteristic 1′-CH ₃ signal. A first order rate law of 1n [A] _t = 1n [A] ₀ -k _obs × t was found for all deuterolysis kinetics. The hydrolysis constants given are mean values from three series of measurements with the compound from Example 1.

Checking the cytotoxic effectiveness in the cell culture test

With the ketophosphamide prodrug (compound from Example VII) Untersu Cancer cells from the BIR-M1 cell line, which are responsible for the breast cancer of Marshall rats are derived from and carried out in cell survival Dependence on the pH of the medium and the dose examined. At pH 7.4 as Only a low toxicity was modeled for a normal cell population, at pH 6.2 as a model for a cancer cell population under the conditions of hyperglycemia on the other hand, a survival rate of cancer cells reduced by a factor of <10,000 found at a dose of 10 µg / ml.

A comparison of the IC ₁₀ at pH 7.4 and at pH 6.2 showed a ratio of the required amounts of substance of 100: 1; ie to destroy 90% of the cell population at pH 7.4 (pH value of the normal cell) 100 times the amount of the compound from Example VII as at pH 6.2 (pH value of a malignant tumor with hyperglycemia) is required.

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically acceptable excipients one or more Contain compounds of formula (I) or those of one or more active ingredient fen of formula (I) exist, and processes for the preparation of these preparations.

The active compounds of the formula (I) are intended to be used in the pharmaceuticals listed above Preparations, preferably in a concentration of about 0.1 to 99.5, preferably from about 0.5 to 95% by weight of the total mixture.  

The pharmaceutical preparations listed above can be used in addition to the verbin of formula (I) also contain other active pharmaceutical ingredients.

The pharmaceutical preparations listed above are produced in customarily by known methods, e.g. B. by dissolving the active ingredient (s) in a solvent, preferably a slightly basic aqueous buffer.

In general, it has been found in both human and veterinary medicine proven advantageous, the active ingredient (s) according to the invention in total gene from about 0.5 to about 500, preferably 1 to 150 mg / kg body weight per 24th Hours, if necessary in the form of several individual doses, to achieve the ge to deliver the desired results. A single dose contains the Active ingredients preferably in amounts of about 1 to about 100, in particular 1 to 80 mg / kg Body weight. However, it may be necessary from the dosie mentioned deviations, depending on the type and body weight the object to be treated, the type and severity of the disease, the type of Preparation and application of the drug as well as the period or inter vall, within which the administration takes place.  

Abbreviations in the experimental part

PPTS = pyridinium p-toluenesulfonate
ET ₃ N = triethylamine
tBuOCH ₃ = tert-butyl methyl ether
PE = petroleum ether
SiMe ₂ tBu = tert-butyl-dimethylsilyl
SiPh ₂ OtBu = tert-butoxy-diphenylsilyl
TBAF = tributylammonium fluoride
CSA = camphorsulfonic acid
TFA = trifluoroacetic acid

General working instruction 1 (implementation of the connections of the general Formulas (IV) and (V) → (VI) Addition of partially protected carbohydrates to exo-methylene enol ether (PPTS catalysis)

In a heated and argon-vented round bottom flask with 200 mg molecular sieve 4 A, 1.00 mg of the hydroxy compound (general formula IV) in 4 ml of dry methylene chloride, 63 mg (0.25 mmol) of pyridinium p-toluenesulfonate (PPTS) and 1.00-2.50 mmol of the exo-methylene enol ether (general formula V) and stirred at room temperature (reaction time: 20-60 min for β-alkoxyenol ether). The reaction is stopped by adding 0.1 ml of Et ₃ N and immediately filtered through 4 g of silica gel (32-63 μm, 100 ml of tBuOMe). The oil obtained after concentration is chromatographed on 40 g of silica gel (32-63 μm, tBuOMe / PE 2: 3, 0.7% Et ₃ N) and dried in a high vacuum (<0.5 torr).

General working instructions 2 Desilylation of siloxy-substituted acetals (general formula VI)

To 1.00 mmol of the siloxy compound (general formula VI), dissolved in 10 ml of THF, 694 mg (2.20 mmol) of tetrabutylammonium fluoride × 3 H ₂ O are added at 0.degree. C., the mixture is stirred for 5-10 min at this temperature and is allowed to according to protective group z. B. 18-22 h (SiMe ₂ tBu) or z. B. 30-45 min (SiPh ₂ OtBu) at room temperature. Filtration over 3 g of silica gel (32-63 µm, tBuOMe / ethanol 10: 1, 0.7% Et ₃ N) and chromatography on 50 g of silica gel (32-63 µm, tBuOMe / PE / ethanol 10: 5: 1, 0 , 7% Et ₃ N) gives the hydroxy compound.

General working instructions 3 Synthesis of phosphoric acid diamidates Implementation of the compounds of the general formulas (II) and (III) → (I)

1.00 mmol of the hydroxy compound, dissolved in 20 ml of abs. 560 µl (4.00 mmol) Et ₃ N and 120 µl (1.50 mmol) N-methylimidazole are added to methylene chloride. At 0 ° C, 388 mg (1.50 mmol) of N, N-bis- (2-chloroethyl) -phosphoric acid amide dichloride are added and the mixture is stirred at + 5 ° C for 16 h (TLC control: tBuOMe / hexane / EtOAc 3: 1: 6, R _F (monochloramide) = 1.0 to 1.5 × R _f (hydroxy compound)). If the implementation is not complete, 0.5 eq. N-methylimidazole / phosphoric acid amide dichloride added. A strong, dry NH ₃ stream is then passed through for 1-2 h (TLC control: tBuOMe / hexane / EtOAc 3: 1: 6, R _f (diamidate) = 0.2 to 0.3 × R _f ( Hydroxyverbin dung)). Most of the precipitated salts are removed by filtration through silica gel (32-63 µm, 3 g, tBuOMe / EtOH 10: 1, 0.7% Et ₃ N). Flash chromatography on silica gel (32-63 µm, 40 g, tBuOMe / PE / EtOH 10: 1: 1, 0.7% Et ₃ N) gives the product after concentration and drying in a high vacuum as a white to slightly yellow solidified foam.

General working instructions 4 Deacetylation of peracetylated ketophosphamide acetals

A mixture of 0.20 mmol of the peracetylated carbohydrate acetal in 1 ml of methanol and 500 mg of Amberlyst A26 ion exchanger (strongly basic, C1 form) is treated with ultrasound for 40 min. The methanolic solution is pipetted and the ion exchanger is washed several times with methanol. Product adhering to the ion exchanger is brought into solution by 5-10 minute ultrasound treatment. Evaporation of the solvent and column filtration on 2 g of silica gel (32-63 µm, tBuOMe / Pe / methanol 6: 1: 2, 0.7% Et ₃ N) give the product.

Output connections Example I Methyl 2,3,4-tri-O-acetyl-α-D-glucopyranoside

10.8 g (19.2 mmol) methyl-2,3,4-tri-O-acetyl-6-O-trityl-α-D-glucopyranoside are dissolved in 100 ml 1-butanol / CH ₂ Cl ₂ (5: 1) dissolved, carefully mixed with 30 ml 90% TFA and after 30 min at 0 ° C with 200 ml sat. K ₂ CO ₃ solution neutralized. Extraction with EtOAc, washing with sat. After drying over Na ₂ SO ₄ and concentrating, the K ₂ CO ₃ and NaCl solution give a crystalline crude product. Chromatography on silica gel (130 g, EtOAc / PE 1: 1) gives 3.74 g (62%) of the title compound as colorless crystals and 685 mg (11%) methyl-2,3,6-tri-O-acetyl-α -D-glucopyranoside as a colorless oil.
Mp .: 105-107 ° C (ether / PE) [α] = +141 (c = 1, chloroform)

Example II Methyl-6-O - [(1RS) -3- (tert-butoxy-diphenylsiloxy) -1-methoxy-1-methyl-ropyl] - 2,3,4-tri-O-acetyl-α-D-glucopyranoside

548 mg (1.71 mmol) of the compound from Example I are, according to Working Instructions 1, with 979 mg (2.74 mmol) of 4- (tert-butoxy-diphenylsilyl) -2-methoxy-but-1-ene and 107 mg (0.43 mmol) PPTS reacted in 15 ml of anhydrous methylene chloride. Reaction time 30 min, chromatography on 130 g of silica gel (32-63 μm, tBuOMe / Pe 2: 3, 0.7% Et ₃ N).
Yield: 959 mg (83% of theory) of a colorless oil.
R _f = 0.28 (tBuOMe / hexane 2: 3) [α] = +74.8 (c = 1, acetone)

Example III Methyl-6-O - [(1RS) -1-methoxy-3-hydroxy-1-methylpropyl] -2,3,4-tri-O-ac-ethyl-α-D- glucopyranoside

2.09 g (3.08 mmol) of the compound from Example II in 20 ml of THF are desilylated in accordance with procedure 2 with 1.17 g (3.70 mmol) of TBAF × 3 H ₂ O. Reaction time: 50 min at room temperature, chromatography on 50 g of silica gel (32-63 mm, tBuOMe / PE 4: 1, then tBuOMe / ethanol 10.1, 0.7% Et ₃ N).
Yield: 1.14 g (88% of theory) of a colorless oil.
R _f = 0.25 (tBuOMe / hexane / ethanol 10: 5: 1). [Α] = +50.7 (c = 1, acetone)

Manufacturing examples example 1 Methyl-6-O - [(P-RS, 1RS) -3- [N, N-bis (2-chloroethyl) diamidophosphato] -1 - meth oxy-1-methylpropyl] -2,3,4-tri-O-acetyl-α-D-glucopyranoside

1.14 g (2.71 mmol) of the compound from Example III are in the presence of 2.26 ml (16.3 mmol) of triethylamine and 0.32 ml (4.07 mmol) of N-methylimidazole with 1.05 g ( 4.07 mmol) of N, N-bis- (2-chloroethyl) -phosphoric acid amide dichloride in 10 ml of methylene chloride phosphorylated 5 h according to procedure 3 and then NH ₃ gas was introduced. Chromatography on 80 g of silica gel (32-63 μm, tBuOMe / PE / ethanol 20: 1: 1, 0.7% Et ₃ N).
Yield: 1.14 g (67% of theory) of a light yellow oil
R _f = 0.10 (tBuOMe / Hexane / EtOAc 3: 1: 6) [α] = +71.2 (c = 1, acetone)

Example 2 Methyl-6-O - [(P-RS, 1RS) -3- [N, N-bis (2-chloroethyl) diamidophosphato] -1 - meth oxy-1-methylpropyl] -α-D-glucopyranoside

74.0 mg (118 μmol) of the compound from Example 1 are deacetylated in 150 μl of methanol with 400 mg of Amberlyst A 26 in accordance with procedure 4.
Yield: 51.6 mg (88% of theory) of white, solidified foam.
R _f = 0.45 (CHCl ₃ / methanol / hexane 6: 2: 1) [α] = +67.2 (c = 1, methanol)

Claims (6)

1. Compounds of the general formula (I), in which
R ¹ , R ² , R ³ and R ^{4 are} identical or different and represent hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or a hydroxyl protective group,
R ^{5 represents} straight-chain or branched alkyl having up to 8 carbon atoms,
R ^{6 represents} straight-chain or branched alkyl having up to 8 carbon atoms,
R ⁷ and R ^{8 are} identical or different and stand for hydrogen or for straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by chlorine,
and wherein the sugar residue stands for aldohexoses and the corresponding pyranosi and can be present both in the D or L form and with the α or β configuration at the anomeric center. 2. Compounds of the general formula (I) according to Claim 1,
in which
R ¹ , R ² , R ³ and R ^{4 are the} same or different and represent hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or acetyl, benzyl or benzoyl,
R ^{5 represents} straight-chain or branched alkyl having up to 6 carbon atoms,
R ^{6 represents} straight-chain or branched alkyl having up to 6 carbon atoms,
R ⁷ and R ^{8 are the} same or different and stand for hydrogen or for straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by chlorine
and wherein the sugar residue stands for aldohexoses and the corresponding pyranosi and can be present both in the D or L form and with the α or β configuration at the anomeric center. 3. Compounds of the general formula (I) according to claim 1,
in which
R ¹ , R ² , R ³ and R ^{4 are the} same or different and represent hydrogen, straight-chain or branched alkyl having up to 3 carbon atoms or acetyl, benzyl or benzoyl,
R ^{5 represents} straight-chain or branched alkyl having up to 4 carbon atoms,
R ^{6 represents} straight-chain or branched alkyl having up to 4 carbon atoms,
R ⁷ and R ^{8 are} identical or different and stand for hydrogen or for straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by chlorine,
and wherein the sugar residue stands for aldohexoses and the corresponding pyranosi and can be present both in the D or L form and with the α or β configuration at the anomeric center. 4. Compounds of the general formula (I) according to claim 1,
in which
R ¹ , R ² , R ³ and R ^{4 are} identical or different and represent hydrogen, methyl, ethyl or acetyl,
R ^{5 represents} methyl or ethyl,
R ^{6 represents} methyl,
R ⁷ and R ^{8 represent} hydrogen
and wherein the sugar residue stands for D-glucose with an α or β configuration at the anomeric center. 5. A process for the preparation of the compounds of general formula (I) according to claim 1, characterized in that
Compounds of the general formula (II) in which
R ^{1 '} , R ^2' , R ^{3 '} and R ^{4' have} the meaning given above of R ¹ , R ² , R ³ and R ⁴ , but do not represent hydrogen
and
R ⁵ and R ^{6 have} the meaning given in Claims 1 to 4,
with N, N-bis (2-chloroethyl) phosphoric acid amide dichloride of the formula (III) Cl ₂ P (O) N (CH ₂ CH ₂ Cl) ₂ (III) in inert solvents, in the presence of a base and an auxiliary,
then carries out ammonolysis,
and in the event that R ⁷ and / or R ^{8 are} not hydrogen, the above-mentioned other substituents are introduced by customary methods,
and in a last step optionally by splitting off the protective group R ^{2 '} , R ^3' , R ^{4 '} and / or R ^1' releases the hydroxy functions. 6. Medicament containing one or more compounds of claims 1 to 4.